The present invention relates to the use of pharmaceutically active derivatives of N-phenylbenzamide for the preparation of a medicament for the treatment of Chronic Obstructive Pulmonary Disease (COPD).
COPD is a major and growing global health problem, it is predicted to become the fifth most common cause of disability in the world by 2020, and it is an increasingly common cause of hospital admission as well. The lack of effective therapeutic agents for treating this disease prompted a lot of efforts within the scientific community in order to identify appropriate pharmacological agents able to satisfactorily address this disease.
Based on current knowledge (National Institute of Health, National Heart, Lung and Blood Institute: GOLD, Global Initiative for Chronic Obstructive Lung Disease: Global Strategy for Diagnosis, Management and Prevention of Chronic Obstructive Pulmonary Disease; update 2003), COPD is a disease state characterized by airflow limitation that is not fully reversible. The airflow limitation is usually both progressive and associated with an abnormal inflammatory response of the lungs to noxious particles or gases, most often related to cigarette smoking. Symptoms, functional abnormalities and complications of COPD can all be explained on the basis on this underlying inflammation and the resulting pathology. The chronic airflow limitation characteristic of COPD is caused by a mixture of small airway disease (obstructive bronchiolitis) and parenchymal destruction (emphysema), the relative contributions of which vary from the person to person. Chronic inflammation causes remodelling and narrowing of the small airways. Destruction of the lung parenchyma, also by inflammatory processes, leads to the loss of alveolar attachments to the small airways and decreases lung elastic recoil; in turn, these changes diminish the ability of the airways to remain open during expiration. The terms “emphysema” and “chronic bronchitis” are frequently used clinically and included in the definition of COPD. Emphysema, or destruction of the gas-exchanging surfaces of the lung (alveoli), describes one of several structural abnormalities present in patients with COPD. Chronic bronchitis, or the presence of cough and sputum production for at least 3 months in each of two consecutive years, remains a clinically and epidemiologically useful term. However, it does not reflect the major impact of airflow limitation on morbidity and mortality in COPD patients. Therefore, the term COPD correctly defines this disease overall.
As anticipated above, COPD is delineated by chronic inflammation throughout the airways, parenchyma, and pulmonary vasculature. The intensity as well as the cellular and molecular characteristics of the inflammation vary as the disease progresses. Over time, inflammation damages the lungs and leads to the pathologic changes characteristic of COPD (Sutherland E. R. et al. Management of Chronic Obstructive Pulmonary Disease. N. Engl. J. Med. 2004; 350: 2689-97; Hogg J. C. et al. The nature of small-airway obstruction in Chronic Obstructive Pulmonary Disease. N. Engl. J. Med. 2004;350: 2645-53).
In fact, COPD is characterised by an increase in neutrophils, macrophages, and T lymphocytes (especially CD8+) in various parts of the lungs. There may also be an increase in eosinophils in some patients, particularly during exacerbations. These increases are brought about by increases in inflammatory cell recruitment, survival, and/or activation. Many studies reveal a correlation between the number of inflammatory cells of various types in the lung and the severity of COPD.
Pharmacological therapy is used to prevent and control symptoms, reduce the frequency and severity of exacerbations, improve health status, and improve exercise tolerance. Therefore, treatment of COPD heavily depends on anti-inflammatory and bronchodilator drugs.
None of the existing medications for COPD have been shown to modify the long-term decline in lung function that is the hallmark of this disease.
The previous International Patent application WO 90/09989 from our group, refers to N-phenylbenzamide derivatives of Formula (I):
where R1 is cyano, nitro, halogen, hydroxy, C1-C4 alkyl, methoxy or tetrazol-5-yl group, R2 is hydrogen, hydroxy or methoxy, R3 is a tetrazol-5-yl group or hydrogen, R4 and R5 are hydrogen if R3 is tetrazol-5-yl group, or R4 and R5 are independently selected from the group consisting of carboxy, methoxycarbonyl, ethoxycarbonyl and carbamoyl if R3 is hydrogen, and R6 is hydrogen or methyl.
These compounds have been claimed in WO 90/09989 for controlling gastric secretion and as protective agents for gastro-enteric mucous membrane.
Finally, compounds of formula (I) have been mentioned as suitable agents for pharmacological treatment of various conditions which can be attributed to hypersensitivity to allergens, such as bronchial asthma, allergic rhinitis, and conjunctivitis.
Among compounds of Formula (I), the derivative of formula (Ia), [N-4-(1H-tetrazol-5-yl)phenyl-4-(1H-tetrazol-5-yl)benzamide], Andolast, CR2039, in which R2, R4, R5 and R6 are hydrogen and R1 and R3 are tetrazol-5-yl groups, was found endowed with pharmacological properties particularly promising for the treatment of asthma (Revel L. et al. CR 2039, a new bis-(1H-tetrazol-5-yl)phenylbenzamide derivative with potential for the topical treatment of asthma. Eur. J. Pharmacol. 1992; 229: 45-53). Suitable pharmaceutical formulations for the use of compound (Ia) in the treatment of asthma have been described in U.S. Pat. No. 5,976,576.
Compound of Formula (Ia) (Andolast, CR2039):
Asthma is the other major chronic obstructive disease of the airways characterised by an underlying airway inflammation. Asthma and COPD have their major symptoms in common, but these are generally more variable in asthma than in COPD. In addition, airflow limitation in asthma is most often completely reversible, either spontaneously or with treatment, while in COPD it is never fully reversible and is usually progressive if exposure to noxius agents continues. In asthma, there is also more evidence of airway hyperresponsiveness (AHR), i.e. of an abnormal bronchoconstrictor response to stimuli.
The underlying chronic airway inflammation is also very different: that in asthma is mainly eosinophilic and driven by CD4+ T lymphocytes, particularly of the Th2 subpopulation, which release a family of proinflammatory cytokines including IL-4, IL-5 and IL-13. Conversely, the chronic inflammation in COPD is neutrophilic and characterised by the presence of increased numbers of macrophages and CD8+ T lymphocytes.
Finally, the responses to treatment of asthma and COPD are dramatically different. Despite the major chronic inflammatory component in both conditions, corticosteroids are significantly more effective in asthma than in COPD, the latter being more sensitive to bronchodilators such as β2 adrenergic agonists and anticholinergics.
The limited value of corticosteroids in reducing inflammation in COPD suggests that novel types of nonsteroidal anti-inflammatory treatment may be needed. There are several new approaches to anti-inflammatory treatment in COPD including, for example, phosphodiesterase inhibitors, transcription factor NF-KB inhibitors, adhesion molecule blockers, matrix metalloproteinase inhibitors, and potassium (K+) channel openers. The latter have several characteristics that will be beneficial in COPD, as it will be described below.
The pharmacological activity of compounds of formula (I) and particularly of compound (Ia) was thought to be mainly due to anti-allergic proprieties of this class of compounds which have been proved to block histamine release (Makovec F. et al. Antiallergic and cytoprotective activity of new N-phenylbenzamido acid derivatives. J. Med. Chem. 1992; 35:3633-40), hence their clinical indication for allergic rhinitis and asthma treatment.
Unexpected pharmacological findings now indicate that compounds of Formula (I) as defined above and in particular compound (Ia), Andolast, relieve the different components of the airways inflammatory response, acting through a previously not identified mechanism.
In fact, Andolast decreases both antibody-mediated and cell-mediated inflammatory responses in atopic subjects.
With respect to the former, Andolast has shown a potent inhibitory effect on IL-4 dependent IgE synthesis by human B lymphocytes from allergic donors. This effect leads to the decrease in allergen-triggered mast cell sensitisation and consequently to the inhibition of IgE-dependent mediator release, including histamine, which is responsible for airway inflammation and AHR in atopic bronchial asthma.
With respect to cell-mediated processes, data from atopic mild-moderate asthmatic patients indicated that a standard treatment course with Andolast is able to induce an inhibitory effect on T lymphocytes (Th2) production of the eosinophil recruiter cytokine IL-5, with a consequent decrease in the percentage of eosinophils in the sputum. Since these cell-mediated processes are effective in both atopic and non-atopic subjects, this effect may contribute to the decrease in airway inflammation and AHR in both kind of patients.
In accordance with the present invention, it has now been surprisingly found that compounds of Formula (I) as defined above are endowed with excellent activity in the activation of calcium (Ca2+)-dependent K+ channels, thus highlighting these compounds as unexpectedly suitable pharmacological agents particularly for the treatment of COPD, as it will be detailed below.